Perinatal asphyxia resulting in newborn hypoxic-ischemic encephalopathy (NHIE) occurs in between 2 to 9/1000 live term newborns. A vastly higher number of preterm babies (60/1000 live preterm babies) also suffer from this condition. In addition to inflicting direct brain damage, leading to acute brain dysfunction, such an insult can also interfere with brain development, determining long-term morbidity.
Worldwide approximately 2 million babies die or remain with long-lasting disability because of NHIE each year.
Despite the continuous progress in Neonatology and Perinatology recently, the aforementioned numbers have not substantially changed. Thus, NHIE remains as the main cause of acquired neonatal neurological impairment of babies worldwide.
Management of NHIE is determined by its complex pathophysiology. After the early energetic fall during hypoxia-ischemia, failure of neuronal ionic pumps lead to a toxic increase of intracellular calcium, activating degrading enzymes. There is also an increase in extracellular excitotoxic substances such as glutamate, which further increases calcium influx.
During reperfusion, re-oxygenation and inflammatory responses start a second wave of damage, which lead to a secondary energetic failure and to DNA damage, activating apoptosis.
Substances within the body such as heat shock proteins, antiapoptotic proteins, neural growth factors and endocannabinoids are able to act as natural neuroprotective and neuro-regenerative substances. However in the majority of cases lack of treatment results in severe brain damage or death.
The immature brain is particularly susceptible to hypoxic-ischemic damage because of a higher sensitivity to glutamate, cytokines and oxidative stress, and the preponderance of pro-apoptotic mechanisms.
Hypoxic-ischemic (HI) damage may affect the fetus at various stages of fetal development, or it can affect the newborn during labour and delivery and in the postnatal period.
Problems during pregnancy may include preeclampsia, maternal diabetes with vascular disease, congenital fetal infections, drug/alcohol abuse, severe fetal anemia, cardiac disease, lung malformations, or problems with blood flow to the placenta.
Problems during labour and delivery can include umbilical cord occlusion, torsion or prolapse, rupture of the placenta or uterus, excessive bleeding from the placenta, abnormal fetal position such as the breech position, prolonged late stages of labour, or very low blood pressure in the mother.
Problems after delivery can include severe prematurity, severe lung or heart disease, serious infections, trauma to the brain or skull, congenital malformations of the brain, or very low blood pressure in the baby.
There is a “temporary therapeutic window” between the HI insult and the irreversible secondary energetic failure, which determines the possibility of a therapeutic strategy leading to the reduction of HI brain damage. Such a strategy has to act on several factors, including excitotoxicity, oxidative stress and inflammation.
Therapeutic hypothermia has been demonstrated to be a useful treatment of NHIE and has become the only therapy with a proven neuroprotective effect in human newborns. Unfortunately, these benefits are partial and only successful in mild cases.
Recent clinical trials in newborns have demonstrated that induced moderate hypothermia reduces the combined outcome of mortality and long-term neurodevelopmental disability at 12-24 months of age. Aside from hypothermia, no established therapies exist.
Hypothermia does not completely protect an injured brain; newborns with the most severe forms of HI injury are often not successfully treated.
The addition of other therapies added during or after hypothermia that can improve neuroprotection, by extending the therapeutic window or providing long-lasting additive or synergistic protection, are needed (Cilio and Ferriero, 2010). However it is important to consider that drugs administered during the neonatal period may be toxic to the immature brain. Excretion of many drugs and their metabolites can be modified by hypothermia, and thus failure of liver and kidney clearance due to HI injury could exacerbate any toxicity.
Anti-epileptic drugs (AED) have been used in combination with hypothermia mainly because seizures are commonly associated with HIE. The AED Topiramate has shown some synergy with hypothermia in animal models if used immediately after the HI event, however the dose used was well above that used for treatment of epilepsy in children.
Indeed Cilio and Ferriero suggest agents such as xenon; N-acetylcysteine; erthyropoietin, melatonin and cannabinoids might augment the protection from hypothermia.
The applicant proposed that since cannabinoids reduce calcium influx and glutamate release, are antioxidant and anti-inflammatory substances, modulate MAP kinase pathways, induce hypothermia and promote neuro-regeneration they might be used in the treatment of NHIE. Many of these effects, however, are due to CB1 receptor activation. In immature brains, over activation of CB1 receptors is known to increase apoptosis. Thus, CB1 agonists are not suitable for neuroprotection in NHIE.
The non-psychoactive cannabinoid cannabidiol (CBD) is of great interest because its effects are CB1-independent. Indeed CBD has been shown to reduce histological and biochemical brain damage in in vivo and in vitro models of NHIE (Alvarez et al., 2008). This cannabinoid has also been shown to provide beneficial effects for at least 3 days post the HI event (Lafeunte et al., 2011).
Additionally the United Kingdom patent GB 2,434,312 describes the neuroprotective properties of a CBD plant extract.
Currently the lack of useful treatments to augment therapeutic hypothermia mean a considerable financial and lifelong personal burden on society and the affected families of newborns suffering from NHIE. Therefore there is an urgent need to improve the outcome for these infants.
Surprisingly, the combination of therapeutic hypothermia with the cannabinoid CBD has been shown to be synergistic in neuroprotection following HI injury in an animal model of NHIE, and as such offers a beneficial treatment option for NHIE.